Dysregulation of Cav1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2

Mutations in the gene encoding Ca(v)1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Ca(v)1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Ca(v)1.4 channels. Whether defects in PR synapse development due to altered Ca(v)1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Ca(v)1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Ca(v)1.4-selective antibodies, we found that Ca(v)1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Ca(v)1.4 activation is either enhanced (Ca(v)1.4(I756T)) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Ca(v)1.4(I756T) and CaBP4 KO mice. Our results demonstrate the importance of proper Ca(v)1.4 function for efficient PR synapse maturation, and that dysregulation of Ca(v)1.4 channels in CSNB2 may have synaptopathic consequences.